Project Summary Humans vary considerably in their sensitivity to rewarding events, with some individuals exhibiting blunted responses to reward and other individuals exhibiting exaggerated responses to reward. Both patterns of aberrant reward sensitivity have been linked to substance use disorders, suggesting that distinct mechanisms may lead to a common clinical outcome. Many of these observations, however, are based on self-report and behavioral measures of reward sensitivity, which may be insensitive to subtle patterns of pathophysiology in humans. Indeed, animal studies have suggested that the underlying pathophysiology in substance use related disorders may be tied to striatal function and its connections with prefrontal cortex. Yet, the striatal response to reward is highly sensitive to social context, such as the presence of a peer. Indeed, drugs of abuse are often sought out and consumed in social contexts or as a result of positive and negative social experiences. Thus, striatal responses to social context (e.g., sharing a reward with a peer) and social reward (e.g., peer acceptance) may play a key role in substance use disorders, potentially shaping how hypersensitivity and hyposensitivity to reward can both lead to drug use. To investigate this possibility, we will study college-aged participants with a wide range of individual differences in self-reported reward sensitivity. We anticipate that self-reported reward sensitivity will have a nonlinear relationship with clinical assessments of substance use, with hypersensitive and hyposensitive individuals exhibiting the highest levels of substance use. Each participant will engage in well- characterized tasks that probe responses to social and nonsocial reward while undergoing functional magnetic resonance imaging (fMRI). We predict that substance use will be tied to distinct patterns of striatal dysfunction (Aim 1). Specifically, hyposensitive individuals will exhibit blunted striatal responses to reward and enhanced connectivity with orbitofrontal cortex; in contrast, hypersensitive individuals will exhibit enhanced striatal responses to reward and blunted connectivity with orbitofrontal cortex. We will also examine the relation between of self-reported reward sensitivity, substance use, and striatal responses to social reward and social context (Aim 2). We hypothesize that individuals reporting the highest levels of substance use will show exaggerated striatal responses to social reward (e.g., peer acceptance relative to rejection) and social context (i.e., sharing a reward with a friend relative to a stranger), independent of self-reported reward sensitivity. This observation would highlight a common neural pathway to substance use. Taken together, our study will help characterize the relation between reward sensitivity and substance use while also providing a foundation for larger projects focused on understanding risk factors and interventions.